NM_000527.5:c.651TGG[1]

CA023734

226329 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: f93a6a4d-f43a-4d61-ab69-e4a067024147

Approved on: 2022-06-02

Published on: 2022-06-30

HGVS expressions

NM_000527.5:c.651TGG[1]
NC_000019.10:g.11105560_11105562del
CM000681.2:g.11105560_11105562del
NC_000019.9:g.11216236_11216238del
CM000681.1:g.11216236_11216238del
NC_000019.8:g.11077236_11077238del
NG_009060.1:g.21180_21182del
ENST00000252444.10:c.912_914del
ENST00000559340.2:c.654_656del
ENST00000560467.2:c.654_656del
ENST00000558518.6:c.654_656del
ENST00000252444.9:c.908_910del
ENST00000455727.6:c.314-1832_314-1830del
ENST00000535915.5:c.531_533del
ENST00000545707.5:c.314-1005_314-1003del
ENST00000557933.5:c.654_656del
ENST00000558013.5:c.654_656del
ENST00000558518.5:c.654_656del
ENST00000560467.1:c.254_256del
NM_000527.4:c.654_656del
NM_001195798.1:c.654_656del
NM_001195799.1:c.531_533del
NM_001195800.1:c.314-1832_314-1830del
NM_001195803.1:c.314-1005_314-1003del
NM_000527.5:c.654_656del
NM_001195798.2:c.654_656del
NM_001195799.2:c.531_533del
NM_001195800.2:c.314-1832_314-1830del
NM_001195803.2:c.314-1005_314-1003del

Pathogenic

• Met criteria codes: PS3_Moderate PM2 PM4 PP1_Strong PS4 PP4

• Not Met criteria codes: BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2 PM6 PM1 PM3 PM5 PS1 PS2 BA1 PP2 PP3 PVS1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS3_moderate, PS4, PM2, PM4 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PP1_strong - Variant segregates with phenotype in 9 informative meiosis in 5 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)): 9 affected family members have the variant. PS3_moderate - PMID: 2088165 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: <2% LDLR activity. PS4 - Variant meets PM2. Variant identified in 10 unrelated index cases (1 case with DLCN ≥ 6 from Robarts Research Institute; 2 cases with DLCN ≥ 6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 4 cases with Simon Broome possible/definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with DLCN ≥ 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 cases with Simon Broome possible/definite FH from GeneDx Inc. PM2 - PopMax MAF = 0.000008826 (0.0008826%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PM4 - Variant meets PM2 and is in frame deletion. PP4 - Variant meets PM2. Identified in 4 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome possible/definite FH, after alternative causes of high cholesterol were excluded.

Met criteria codes

• PS3_Moderate: PMID: 2088165 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: <2% LDLR activity.
• PM2: PopMax MAF = 0.000008826 (0.0008826%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).
• PM4: Variant meets PM2 and is in frame deletion.
• PP1_Strong: Variant segregates with phenotype in 9 informative meiosis in 5 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)): 9 affected family members have the variant.
• PS4: Variant meets PM2. Variant identified in 10 unrelated index cases (1 case with DLCN ≥ 6 from Robarts Research Institute; 2 cases with DLCN ≥ 6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 4 cases with Simon Broome possible/definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with DLCN ≥ 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 cases with Simon Broome possible/definite FH from GeneDx Inc.
• PP4: Variant meets PM2. Identified in 4 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome possible/definite FH, after alternative causes of high cholesterol were excluded.

Not Met criteria codes

• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline